ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the epsilon 4 allele of the APOE gene significantly increases AD risk, the epsilon 2 allele is protective relative to the common epsilon 3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-beta (A beta) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple A beta-related or A beta-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.

Automated summary

Alzheimer's disease is the most common cause of dementia worldwide, and the APOE gene is the strongest and most prevalent genetic risk factor. The ε4 allele increases AD risk while the ε2 allele is protective. ApoE protein has multiple functions, including lipid transport and promoting the formation of amyloid-beta plaques. Different apoE isoforms have different effects on Aβ-related pathways. The complexity of apoE biology presents challenges to developing effective therapeutic strategies.